International patent applications including WO 03/029232 and WO 2007/144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof. WHO has since published that vortioxetine is the recommended international Non-proprietary Name (INN) for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetine was formerly referred to in the literature as Lu AA21004. In September and December 2013 FDA and EMA, respectively, approved vortioxetine for the treatment of major depressive disorder/major depressive episode under the trade name Brintellix™. Of particular interest, vortioxetine has also shown effect in elderly suffering from recurrent major depressive disorder [Int. Clin. Psychopharm., 27, 215-227, 2012].
Vortioxetine is an antagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist on the 5-HT1A receptor and a partial agonist on the 5-HT1B receptor and an inhibitor of the serotonin transporter. Additionally, vortioxetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur. Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012]. The pharmacological profile gives reason to believe that vortioxetine may have a pro-cognitive effect. This notion seems to be supported by clinical evidence where vortioxetine has been shown to have a direct beneficial effect on cognition independent of its antidepressive effects [Int. Clin. Psychopharm., 27, 215-227, 2012; Int J neurophychopharm 17, 1557-1567, 2014; Neuropsychopharmacol, 40, 2025-2037, 2015.
Vortioxetine is available on the market as film coated instant release (IR) tablets containing 5, 10, 15 and 20 mg vortioxetine as the HBr salt and as an oral drop solution comprising 20 mg/ml vortioxetine as the DL lactate salt.
It is well-established that swallowing tablets and capsules may be a problem for a significant number of patients, and this may ultimately lead to lack of compliance with the consequent increased risk of inadequate treatment response or relapse. Studies have shown that every third woman and every sixth man report problems with swallowing tablets. Notably, difficulties with swallowing tablets seem to be more wide-spread in the elderly population and amongst children [Pharm World Sci, 23, 185-188, 2001]. Different technologies have been applied to overcome the problems with swallowing tablets and capsules. For example, alternatives to oral administration may be used, such as parenteral, transdermal, nasal, buccal, sublingual or rectal administration. Alternatively, easy-to-swallow oral administration forms such as oral solutions, oral dispersible tablets, powders or granules to be sprinkled on food or oral gels may be applied.
Gel compositions for oral administration are an attractive alternative to tablets and capsules because they combine the ease and simplicity of oral administration with little or no resistance to swallowing. Due to the inherent decreased stability of pharmaceutical products in liquid or semi-solid (e.g. gel form) compositions, gel compositions are often provided as dry powders which are to be mixed with a liquid, typically water or saliva, immediately prior to use to form the gel. U.S. Pat. No. 6,709,678 discloses a pharmaceutical composition comprising an active ingredient in combination with hydratable polymers, such as alginates or carboxymethylcellulose which upon contact with saliva forms a gel in the mouth. WO 01/76610 discloses a composition comprising vitamin D and starch derivatives which upon mixing with water forms a pudding-like gelled suspension. WO 2005/107713 discloses a composition comprising an active ingredient together with gellan gum which upon addition of water swells or gels to have a texture similar to that of a soft pudding. Such administration form has been developed for commercial use under the trade name Parvulet™. Parvulet™ comes as a spoon preloaded with active ingredient and a gelling polymer and wrapped in foil. The user unwraps the spoon and adds water to form the gel. It is a common characteristic of these technologies that gelling or swelling is obtained by use of gelling polymers. The application of additional excipients in any pharmaceutical composition is always problematic because it increases the risk of lack of compatibility between the active ingredient and the excipients or between excipients.
One aim of the present invention is to provide vortioxetine salts which can be administered as an oral gel without the need for gelling polymers.
WO 2011/023194 and WO 2011/136376 disclose enteric coated (EC) formulations comprising vortioxetine. One aim of the present invention is to provide enteric coated formulations with superior pharmacokinetic properties.